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Wilms’ Tumor
Nephroblastoma Affects 1:10,000 children ~8% of all pediatric Malignancies 80% of these tumors can be successfully
treated
WT1 Tumor Suppressor Chromosome 11 (11p13) Mutated in 5-10% of all Wilms Tumors ~50Kb 10 exons 52-62 kDa 24 Isoforms
WT1
Scholz et al.
WT1
Wagner et al.
Frasier Syndrome
Heterozygous loss of +KTS causes
• Male to Female sex reversal
• Wilms’ Tumor
• Glomerulosclerosis
WAGR SyndromeHeterozygous loss of WT1 Wilms’ Tumor Mental retardation Milder overall phenotype in kidneys and
gonads than DDS and FS
Denys-Drash Syndrome
Truncated Zinc-Fingers
Causes
• normal female gonads
• In males, streak gonads and mild hermaphroditism
• Wilm’s Tumor
Dominant-negative phenotype
Denys-Drash Syndrome
• Wild type WT1 homodimerizes
• Truncated WT1 dimerizes with wild type WT1, which further lowers WT1 function
• Truncated WT1 works in a Dominant-Negative motif
Knockout Mice Embryonic Lethal between 12 days and birth Mice had no Kidneys nor Gonads and defects in
mesothelial tissue, heart, adrenal glands and spleen WT1(+KTS) lacking Mice showed disturbed podocyte
function and male-to-female sex reversal WT1 (-KTS) lacking Mice showed severe kidney and
gonad defects
WT1
Wagner et al.
In Conclusion WT1 is a Tumor Suppressor WT1 has 24 Isoforms WT1 interacts with DNA, RNA and other Proteins WT1 is a Transcription Factor It is an Enhancer It is a Developmental Gene
ReferencesScharnhorst, V., Van der Eb, A., Jochemsen, A. 2001. WT1 proteins:
funtion in growth and differentiation. Gene: 273, p141-161.
Scholz, H., Kirschner, K. 2005. A Role for the Wilm’s Tumor Protein WT1 in Organ Development. Physiology 20: p54-59.
Wagner, K-D., Wagner, N., Schedl, A. 2003. The complex life of WT1. Journal of Cell Science: p1653-1658